Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors

脂蛋白脂肪酶抑制剂的分子机制研究

基本信息

批准号：
9102237
负责人：
Saskia Neher
金额：
$ 37.1万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102237
关键词：
ANGPTL3 gene ANGPTL4 gene Address Affect American Binding Biological Markers Blood C-terminal Cause of Death Drug Design Enzymes Fatty acid glycerol esters Future Genes Goals Health Heart Diseases Human Hypertriglyceridemia Individual Intervention Investigation Kinetics Knowledge Lipids Lipoproteins Liver Mediating Modeling Molecular Molecular Chaperones Molecular Models Mus Mutation Pharmaceutical Preparations Plasma Population Protein Biochemistry Proteins Proteomics Regulation Reporting Resistance Risk Factors Role Scaffolding Protein Serum Site Structure Testing Total Internal Reflection Fluorescent Triglyceride Metabolism Triglycerides United States Variant Very low density lipoprotein blood lipid blood lipoprotein cardiovascular disorder risk design enzyme replacement therapy gain of function gene therapy heart disease risk in vivo inhibitor/antagonist lipoprotein lipase lipoprotein lipase inhibitor molecular modeling mutant novel therapeutic intervention novel therapeutics population based prevent protein protein interaction single molecule therapeutic protein tool uptake

ANGPTL3 gene ANGPTL4 gene Address Affect American Binding Biological Markers Blood C-terminal Cause of Death Drug Design Enzymes Fatty acid glycerol esters Future Genes Goals Health Heart Diseases Human Hypertriglyceridemia Individual Intervention Investigation Kinetics Knowledge Lipids Lipoproteins Liver Mediating Modeling Molecular Molecular Chaperones Molecular Models Mus Mutation Pharmaceutical Preparations Plasma Population Protein Biochemistry Proteins Proteomics Regulation Reporting Resistance Risk Factors Role Scaffolding Protein Serum Site Structure Testing Total Internal Reflection Fluorescent Triglyceride Metabolism Triglycerides United States Variant Very low density lipoprotein blood lipid blood lipoprotein cardiovascular disorder risk design enzyme replacement therapy gain of function gene therapy heart disease risk in vivo inhibitor/antagonist lipoprotein lipase lipoprotein lipase inhibitor molecular modeling mutant novel therapeutic intervention novel therapeutics population based prevent protein protein interaction single molecule therapeutic protein tool uptake

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项目摘要

DESCRIPTION (provided by applicant): Elevated serum triglycerides are associated with increased risk for cardiovascular disease. Lipoprotein lipase (LPL) is a secreted enzyme that clears lipids from the blood by hydrolyzing the triglycerides component of circulating lipoproteins. LPL has a number of macromolecular inhibitors. In human populations, known mutations in these macromolecular inhibitors result in reduced ability to inhibit LPL. As a result, LPL activity is increased and serum triglycerides are decreased. We recently discovered that one of these proteins, ANGPTL4, acts as a reversible, noncompetitive LPL inhibitor rather than an unfolding molecular chaperone as was previously believed. This new understanding of ANGPTL4 function led us to ask if other LPL inhibitors act on LPL using a similar mechanism. This proposal focuses on biochemically defining the LPL/inhibitor interaction. In Aim 1 we will define the sequence motifs and kinetic and molecular mechanisms used by these inhibitors to reduce LPL activity. In Aim 2, we will identify the features on LPL that are recognized by the inhibitors. In Aim 3 we ask why a variant of LPL has enhanced activity in vivo. To achieve these aims we will combine protein biochemistry, structural proteomics and single molecule TIRF microscopy. Successful completion of these aims will provide a precise molecular understanding of the mechanism of LPL activity and regulation. Because of LPL's key role in human triglyceride metabolism, these discoveries hold promise for developing new therapies for hypertriglyceridemia.

描述（由适用提供）：血清甘油三酸酯升高与心血管疾病的风险增加有关。脂蛋白脂肪酶（LPL）是一种分泌的酶，通过水解循环脂蛋白的甘油三酸酯成分来清除血液中的脂质。 LPL具有许多大分子抑制剂。在人类种群中，这些大分子抑制剂中的已知突变导致抑制LPL的能力降低。因此， LPL活性增加，并进行血清甘油三酸酯。我们最近发现，这些蛋白质之一ANGPTL4充当可逆的，无竞争的LPL抑制剂，而不是以前认为的那样展开的分子链。对ANGPTL4功能的新理解使我们询问其他LPL抑制剂是否使用类似的机制对LPL作用。该建议着重于生化定义LPL/抑制剂相互作用。在AIM 1中，我们将定义这些抑制剂用于降低LPL活性的序列基序以及动力学和分子机制。在AIM 2中，我们将确定抑制剂所识别的LPL功能。在AIM 3中，我们询问为什么LPL的变体在体内具有增强的活性。为了实现这些目标，我们将结合蛋白质生物化学，结构蛋白质组学和单分子TIRF显微镜。这些目标的成功完成将提供对LPL活性和调节机制的精确分子理解。由于LPL在人类甘油三酸酯代谢中的关键作用，这些发现有望开发高甘油三酯血症的新疗法。